Our research focuses on the importance of the Bone Morphogenetic Protein Receptor 2 (BMPR2) signaling pathway in pulmonary, pulmonary-vascular as well as cardiac disease.
In 2000 two independent groups discovered mutations in the BMPR2 pathway as the genetic basis for pulmonary arterial hypertension (PAH). Over the past years more mutations either directly involved in the BMPR2 pathway (Endoglin, Alk1, Smad9) or indirectly linked to the BMPR2 pathway (Caveolin-1) have been discovered, emphasizing the central role of BMPR2 signaling in familial PAH. It was subsequently found that reduced BMPR2 expression and signaling seems to be a feature of other sporadic or idiopathic forms of PAH.
Hypothesizing that increasing BMPR2 signaling might improve PAH, we have performed a High-Throughput Screen of FDA approved drugs to find BMPR2 activators and have identified the immunosuppressive drug FK506 (Tacrolimus) as the main activator.
We have subsequently shown that FK506 could rescue endothelial dysfunction in PAH, and prevent and reverse PAH in rodent models of experimental PAH (Spiekerkoetter JCI 2013).
This discovery has lead to the initiation of a phase II clinical trial to test the safety, tolerability and efficacy of low-dose FK506 in PAH at Stanford (clinicaltrials.gov Search for: NCT01647945)
Our most recent Research Goals:
- To find novel ways how to modulate BMPR2 signaling (small molecule HTS screen, identifying novel modifier genes using an siRNA screen).
- To Identify a Biomarker signature that reflects the “BMPR2 status” of a patient
(Collaboration with Dr. Zamanian, Director of the Adult Clinical Hypertension Service, Division of Pulmonary and Critical Care, Stanford University).
- To determine the role of BMPR2 signaling in the development of Right Ventricular Hypertrophy (RVH) and failure, which is the leading cause of death in PAH (Collaboration with Dres Reddy and Bernstein, Pediatric Cardiology, Stanford University).
- To evaluating the importance of BMPR2 signaling in vascular development in neonatal chronic lung disease (Collaboration with Dr. Anne Hilgendorff, Helmholz Institute, Muenchen, Germany).
- To use Public Data to identify a “PAH gene signature” that could be targeted with repurposed existing drugs as a new paradigm to treat pulmonary hypertension (Collaboration with Dr. Kathri, Biomedical Informatics Research, Department of Medicine, Stanford University).
- To develop a computational method to identify drug targets and drugs that elicit adoptive RV hypertrophy using targeted knock-out and overexpression mouse models as well as the chemical-protein links in the STITCH database with the ultimate goal to test those drugs in animal models of Pulmonary Hypertension (Collaboration with Dr. Michel Dumontier, Biomedical Informatics Research and Dr. Haddad, Cardiology, Department of Medicine, Stanford University).
- To use Low-dose FK506 for prevention of invasive bladder cancer (Shin K et al. Hedgehog signaling restrains bladder cancer progression by eliciting stromal production of urothelial differentiation factors. Cancer Cell. 2014 Oct 13;26(4):521-33) (Collaboration with Dr. Philip Beachy, Department of Biochemistry and Dr. Liao, Department of Urology, both at Stanford University)